The present invention is novel compounds which are N-hydroxyamide, N-hydroxyurea, N-hydroxythioamide and N-hydroxythiourea derivatives of fenamate, indomethacin, cycloprofen, oxapinac and indoprofen, and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use therefor. The invention compounds are now found to have activity as dual inhibitors or selective inhibitors of 5-lipoxygenase and cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and the like. Thus, the present invention is also a pharmaceutical composition or method of use therefor.
Specific hydroxamates of fenamic acid are shown in copending U.S. application Ser. No. 134,725 which includes a reference to European Application Publication No. 0,196,184 having broad disclosure of hydroxamic acid derivatives of selected aryl ring systems effective as high potency inhibitors of 5-lipoxygenase. Summers et al also disclosed hydroxamic acid inhibitors of 5-lipoxygenase in an abstract, September, 1987 and J. Med. Chem., 1987, 30, 574-80. Indole, benzofuran and benzothiophine each having an --A--N--C--R.sub.1 substituent is disclosed in European Application Publication No. 0279,263. Additionally various ring systems are known which are attached to a similar N--C containing substituent. For example, a (phenylalkoxy) phenyl; a biphenyl alkyl; a phenyl or naphthyl; 7-oxabicyclo (2.2.1) heptane; dibenzofuran; and (alkoxy) or (phenyloxy)-phenyl and naphthyl or thiofurane are disclosed in European Application Publication No. 279,281, British No. 2,191,194, PCT Application No. GB 86/00791 British No. 2,194,531, U.S. Pat. No. 4,769,387, and European Application Publication No. 292,699 respectively. European Application Publication No. 196,674 also discloses compounds including an -N-C- containing moiety having phenyl, naphthyl or sulfur heterocyclic ring systems attached directly or through various linking groups to the N of the moiety. The J. Org. Chem. 1989, 54, 1221-1223 and J. Med. Chem., 31, 1, pp. 3-5 (Jan. 1988) disclose (hydroxy) or phenylalkoxy)-phenyl, naphthyl and phenoxyphenyl rings in like manner attached to an --N--C-- containing substituent.
However, none of the above noted disclosures describe hydroxamates of the configuration disclosed in this application on the selected nonsteroidal antiinflammatory type substrates.
Thus, the differences between the present invention and the teachings of the references are readily apparent.